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Chronic myelomonocytic leukemia

David P Steensma, MD
Eric Padron, MD
Section Editor
Richard A Larson, MD
Deputy Editor
Alan G Rosmarin, MD


Chronic myelomonocytic leukemia (CMML) is a malignant hematopoietic stem cell disorder with clinical and pathological features of both a myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS). CMML is characterized by a peripheral blood monocytosis accompanied by bone marrow dysplasia; cytopenias and hepatosplenomegaly are common (table 1).

There is a propensity for progression to acute myeloid leukemia (AML), which is defined by ≥20 percent marrow blast cells. Although historically considered a subtype of MDS, CMML is a clinically and genetically distinct entity with a unique clinical presentation and natural history. CMML is among the most aggressive chronic leukemias, and there are fewer effective therapies than for most other hematologic malignancies. However, murine models and genomic data have laid a scientific foundation for the generation of novel therapeutics that is anticipated to broaden treatment options for CMML patients.

The epidemiology, diagnosis, and management of CMML will be reviewed here. Other myeloproliferative neoplasms and myelodysplastic syndromes are presented separately. (See "Overview of the myeloproliferative neoplasms" and "Overview of the treatment of myelodysplastic syndromes" and "Clinical manifestations and diagnosis of the myelodysplastic syndromes".)


The pathogenesis of CMML is poorly understood. CMML is thought to arise via the serial acquisition of somatic genetic events that aggregate by Darwinian principles into distinct neoplastic cell clones [1]. Most cases of CMML appear to comprise more than one clone and are genetically dynamic. Many of the genetic mutations identified in patients with CMML induce a CMML phenotype in murine models [2-5]. Although CMML does have a distinct "genetic fingerprint" (ie, a unique frequency and pattern of mutated genes), there is no single disease-defining mutation or chromosomal abnormality.

The most common cytogenetic abnormalities observed in CMML are rearrangements or deletions of chromosome 7, and trisomy 8 [6]. Marrow and blood cells from most patients with CMML have acquired mutations in genes that encode epigenetic modifiers (eg, TET2, ASXL1, EZH2), regulators of alternative mRNA splicing (eg, SRSF2, SF3B1, ZRSF2), transcription factors (eg, RUNX1), and cytokine signaling (eg, NRAS, CBL, KRAS, JAK2) [7-10]. Similar to the closely related pediatric disease juvenile myelomonocytic leukemia (JMML), a large fraction of CMML cases display hypersensitivity to granulocyte macrophage colony-stimulating factor (GM-CSF) in vitro, which likely contributes to the monocytosis characteristic of the disease [11-13]. These data suggest that the genetic pathogenesis of CMML is complex but converges on a phenotype that is skewed towards monocytic hematopoiesis and GM-CSF hypersensitivity.

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Literature review current through: Nov 2017. | This topic last updated: Apr 07, 2017.
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  1. Itzykson R, Solary E. An evolutionary perspective on chronic myelomonocytic leukemia. Leukemia 2013; 27:1441.
  2. Abdel-Wahab O, Adli M, LaFave LM, et al. ASXL1 mutations promote myeloid transformation through loss of PRC2-mediated gene repression. Cancer Cell 2012; 22:180.
  3. Li Z, Cai X, Cai CL, et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 2011; 118:4509.
  4. Sanada M, Suzuki T, Shih LY, et al. Gain-of-function of mutated C-CBL tumour suppressor in myeloid neoplasms. Nature 2009; 460:904.
  5. Wang J, Liu Y, Li Z, et al. Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood 2010; 116:5991.
  6. Such E, Cervera J, Costa D, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011; 96:375.
  7. Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 2013; 31:2428.
  8. Meggendorfer M, Roller A, Haferlach T, et al. SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 2012; 120:3080.
  9. Gambacorti-Passerini CB, Donadoni C, Parmiani A, et al. Recurrent ETNK1 mutations in atypical chronic myeloid leukemia. Blood 2015; 125:499.
  10. Elena C, Gallì A, Such E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 2016; 128:1408.
  11. Padron E, Painter JS, Kunigal S, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood 2013; 121:5068.
  12. Ramshaw HS, Bardy PG, Lee MA, Lopez AF. Chronic myelomonocytic leukemia requires granulocyte-macrophage colony-stimulating factor for growth in vitro and in vivo. Exp Hematol 2002; 30:1124.
  13. Kotecha N, Flores NJ, Irish JM, et al. Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. Cancer Cell 2008; 14:335.
  14. Itzykson R, Kosmider O, Renneville A, et al. Clonal architecture of chronic myelomonocytic leukemias. Blood 2013; 121:2186.
  15. Yoshida K, Sanada M, Shiraishi Y, et al. Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 2011; 478:64.
  16. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937.
  17. Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood 2008; 112:45.
  18. Osca-Gelis G, Puig-Vives M, Saez M, et al. Population-based incidence of myeloid malignancies: fifteen years of epidemiological data in the province of Girona, Spain. Haematologica 2013; 98:e95.
  19. McQuilten ZK, Wood EM, Polizzotto MN, et al. Underestimation of myelodysplastic syndrome incidence by cancer registries: Results from a population-based data linkage study. Cancer 2014; 120:1686.
  20. Takahashi K, Pemmaraju N, Strati P, et al. Clinical characteristics and outcomes of therapy-related chronic myelomonocytic leukemia. Blood 2013; 122:2807.
  21. Padron E, Yoder S, Kunigal S, et al. ETV6 and signaling gene mutations are associated with secondary transformation of myelodysplastic syndromes to chronic myelomonocytic leukemia. Blood 2014; 123:3675.
  22. Bastida P, García-Miñaúr S, Ezquieta B, et al. Myeloproliferative disorder in Noonan syndrome. J Pediatr Hematol Oncol 2011; 33:e43.
  23. Breccia M, Cannella L, Frustaci A, et al. Chronic myelomonocytic leukemia with antecedent refractory anemia with excess blasts: further evidence for the arbitrary nature of current classification systems. Leuk Lymphoma 2008; 49:1292.
  24. Emanuel PD. Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 2008; 22:1335.
  25. Orazi A, Germing U. The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 2008; 22:1308.
  26. Geary CG, Catovsky D, Wiltshaw E, et al. Chronic myelomonocytic leukaemia. Br J Haematol 1975; 30:289.
  27. Tefferi A, Hoagland HC, Therneau TM, Pierre RV. Chronic myelomonocytic leukemia: natural history and prognostic determinants. Mayo Clin Proc 1989; 64:1246.
  28. Fenaux P, Beuscart R, Lai JL, et al. Prognostic factors in adult chronic myelomonocytic leukemia: an analysis of 107 cases. J Clin Oncol 1988; 6:1417.
  29. Fenaux P, Jouet JP, Zandecki M, et al. Chronic and subacute myelomonocytic leukaemia in the adult: a report of 60 cases with special reference to prognostic factors. Br J Haematol 1987; 65:101.
  30. Duguid JK, Mackie MJ, McVerry BA. Skin infiltration associated with chronic myelomonocytic leukaemia. Br J Haematol 1983; 53:257.
  31. Mufti GJ, Oscier DG, Hamblin TJ, et al. Serous effusions in monocytic leukaemias. Br J Haematol 1984; 58:547.
  32. Youman JD 3rd, Saarni MI, Linman JW. Diagnostic value of muramidase (Lysozyme) in acute leukemia and preleukemia. Mayo Clin Proc 1970; 45:219.
  33. Patel TV, Rennke HG, Sloan JM, et al. A forgotten cause of kidney injury in chronic myelomonocytic leukemia. Am J Kidney Dis 2009; 54:159.
  34. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of Tumors of Haematopoietic and Lymphoid Tissues, IARC Press, Lyon 2008.
  35. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016; 127:2391.
  36. Apperley JF, Gardembas M, Melo JV, et al. Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 2002; 347:481.
  37. Schuler E, Schroeder M, Neukirchen J, et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leuk Res 2014; 38:1413.
  38. Selimoglu-Buet D, Wagner-Ballon O, Saada V, et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood 2015; 125:3618.
  39. Wang SA, Hutchinson L, Tang G, et al. Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components. Am J Hematol 2013; 88:219.
  40. Niemeyer CM, Kratz C. Juvenile myelomonocytic leukemia. Curr Oncol Rep 2003; 5:510.
  41. Koike K, Matsuda K. Recent advances in the pathogenesis and management of juvenile myelomonocytic leukaemia. Br J Haematol 2008; 141:567.
  42. Aricò M, Biondi A, Pui CH. Juvenile myelomonocytic leukemia. Blood 1997; 90:479.
  43. Passmore SJ, Chessells JM, Kempski H, et al. Paediatric myelodysplastic syndromes and juvenile myelomonocytic leukaemia in the UK: a population-based study of incidence and survival. Br J Haematol 2003; 121:758.
  44. Loh ML, Sakai DS, Flotho C, et al. Mutations in CBL occur frequently in juvenile myelomonocytic leukemia. Blood 2009; 114:1859.
  45. De Filippi P, Zecca M, Lisini D, et al. Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia. Br J Haematol 2009; 147:706.
  46. Niemeyer CM, Kang MW, Shin DH, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet 2010; 42:794.
  47. Kato M, Yasui N, Seki M, et al. Aggressive transformation of juvenile myelomonocytic leukemia associated with duplication of oncogenic KRAS due to acquired uniparental disomy. J Pediatr 2013; 162:1285.
  48. Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med 1985; 103:620.
  49. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976; 33:451.
  50. Kantarjian H, O'Brien S, Ravandi F, et al. Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System. Cancer 2008; 113:1351.
  51. Patnaik MM, Padron E, LaBorde RR, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 2013; 27:1504.
  52. Such E, Germing U, Malcovati L, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood 2013; 121:3005.
  53. Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 2014; 28:2206.
  54. Niemeyer CM, Arico M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS). Blood 1997; 89:3534.
  55. Locatelli F, Niemeyer C, Angelucci E, et al. Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol 1997; 15:566.
  56. Zang DY, Deeg HJ, Gooley T, et al. Treatment of chronic myelomonocytic leukaemia by allogeneic marrow transplantation. Br J Haematol 2000; 110:217.
  57. Krishnamurthy P, Lim ZY, Nagi W, et al. Allogeneic haematopoietic SCT for chronic myelomonocytic leukaemia: a single-centre experience. Bone Marrow Transplant 2010; 45:1502.
  58. Kröger N, Zabelina T, Guardiola P, et al. Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2002; 118:67.
  59. Park S, Labopin M, Yakoub-Agha I, et al. Allogeneic stem cell transplantation for chronic myelomonocytic leukemia: a report from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Eur J Haematol 2013; 90:355.
  60. Deeg HJ, Storer B, Slattery JT, et al. Conditioning with targeted busulfan and cyclophosphamide for hemopoietic stem cell transplantation from related and unrelated donors in patients with myelodysplastic syndrome. Blood 2002; 100:1201.
  61. Taussig DC, Davies AJ, Cavenagh JD, et al. Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol 2003; 21:3060.
  62. Davies JK, Taussig DC, Oakervee H, et al. Long-term follow-up after reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia/myelodysplastic syndrome: late CNS relapses despite graft-versus-host disease. J Clin Oncol 2006; 24:e23.
  63. Ho AY, Pagliuca A, Kenyon M, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood 2004; 104:1616.
  64. Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer 2007; 109:713.
  65. Onida F, Barosi G, Leone G, et al. Management recommendations for chronic myelomonocytic leukemia: consensus statements from the SIE, SIES, GITMO groups. Haematologica 2013; 98:1344.
  66. Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood 1996; 88:2480.
  67. Beran M, Kantarjian H, O'Brien S, et al. Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 1996; 88:2473.
  68. Beran M, Estey E, O'Brien S, et al. Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Clin Oncol 1999; 17:2819.
  69. Antonioli E, Guglielmelli P, Pieri L, et al. Hydroxyurea-related toxicity in 3,411 patients with Ph'-negative MPN. Am J Hematol 2012; 87:552.
  70. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer 2006; 106:1794.
  71. Rüter B, Wijermans PW, Lübbert M. Superiority of prolonged low-dose azanucleoside administration? Results of 5-aza-2'-deoxycytidine retreatment in high-risk myelodysplasia patients. Cancer 2006; 106:1744.
  72. Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood 2004; 103:1635.
  73. Kantarjian H, Oki Y, Garcia-Manero G, et al. Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 2007; 109:52.
  74. Kantarjian HM, O'Brien S, Shan J, et al. Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome. Cancer 2007; 109:265.
  75. Kantarjian H, Huang X, Issa JP. Response: Decitabine response with chromosome 7 abnormality in MDS, and decitabine optimal schedule. Blood. 2007; 110:1083.
  76. Braun T, Itzykson R, Renneville A, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011; 118:3824.
  77. Adès L, Sekeres MA, Wolfromm A, et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013; 37:609.
  78. Patnaik MM, Wassie EA, Lasho TL, et al. Blast transformation in chronic myelomonocytic leukemia: Risk factors, genetic features, survival, and treatment outcome. Am J Hematol 2015; 90:411.
  79. Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood 2015; 125:1857.
  80. Doll DC, Kasper LM, Taetle R, List AF. Treatment with low-dose oral etoposide in patients with myelodysplastic syndromes. Leuk Res 1998; 22:7.
  81. Weihrauch MR, Staib P, Seiberlich B, et al. Phase I/II clinical study of topotecan and cytarabine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia. Leuk Lymphoma 2004; 45:699.
  82. Munshi NC, Tricot GJ. Single weekly cytosine arabinoside and oral 6-thioguanine in patients with myelodysplastic syndrome and acute myeloid leukemia. Ann Hematol 1997; 74:111.
  83. Buckstein R, Kerbel R, Cheung M, et al. Lenalidomide and metronomic melphalan for CMML and higher risk MDS: a phase 2 clinical study with biomarkers of angiogenesis. Leuk Res 2014; 38:756.
  84. www.aamds.org/aplastic (Accessed on July 12, 2011).